HIV-1 and highly active antiretroviral treatment (HAART)-Associated Lipodystrophy Syndrome (HALS) is characterized by loss of subcutaneous adipose tissue and accumulation of intra-abdominal adipose tissue1. The syndrome is also commonly accompanied by metabolic abnormalities such as insulin resistance, dyslipidemia, and diabetes mellitus. The pathogenesis of HALS is not entirely understood;it is likely that the use, type and duration of anti-retroviral medications are important in the development and severity of HALS. Insulin resistance and increased intra-abdominal fat are also the major predisposing conditions of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Therefore, it would be expected that patients with HALS, which is characterized by intra-abdominal fat deposition and insulin resistance, would develop hepatic steatosis and steatohepatitis. Indeed, the percentage of liver fat, estimated by nuclear magnetic resonance spectroscopy, was found to be 10 times higher in HIV-infected patients on HAART with lipodystrophy than in HIV-infected patients on HAART without lipodystrophy, and was correlated with insulin resistance. Thus, HALS is characterized by the pathogenetic features of "obesity-related" NAFLD/NASH and has been shown in small studies to be associated with hepatic steatosis and steatohepatitis. However, the clinically relevant question of whether HALS is associated with the development of cirrhosis, likely mediated by NAFLD/NASH, has not been answered to our knowledge. Hepatitis C virus (HCV) co-infection occurs in as many as 25% of HIV-infected patients. Hepatic steatosis is known to be a common and pathogenetic feature of chronic HCV infection causing increased progression to fibrosis and cirrhosis. Therefore, HALS could also promote the progression to cirrhosis in HCV co-infected patients, by inducing hepatic steatosis, but this has never been investigated. If HALS is related to the development of cirrhosis, as we hypothesize, and antiretroviral medications are believed to be central in the pathogenesis of HALS, then it is also be important to investigate whether exposure to antiretroviral medications is associated with the development cirrhosis and whether such an association is mediated by the development of HALS. We hypothesize that HALS is an important risk factor for the development of cirrhosis in HIV-infected patients. This association could have many clinical implications because cirrhosis is the second leading cause of death in HIV-infected persons. We present preliminary data to support this hypothesis and propose to examine it further with the following specific aims: 1. Determine whether there is an association between HALS and the development of cirrhosis among HIV-1-infected patients. 2. Determine whether the association between HALS and cirrhosis is different among HIV-1- infected patients with or without viral hepatitis co-infection. 3. Determine whether specific antiretroviral medications or combinations of medications are associated with the development of cirrhosis in HIV-1-infected patients. Our secondary aim is to investigate whether there are other important modifiers of the association between HALS and cirrhosis, including body mass index, race-ethnicity, and diabetes. We will achieve these aims by analyzing data from the national Veterans Affairs (VA) HIV Clinical Case Registry, which contains clinical data on all diagnosed, HIV-infected patients receiving care in VA facilities throughout the country (n=23,463). This represents one of the largest, comprehensive clinical databases of HIV-infected patients in the world. PUBLIC HEALTH RELEVANCE: We will investigate whether HALS, or antiretroviral medications that can contribute to the development of HALS, are important, novel risk factors for cirrhosis among all diagnosed HIV-infected patients in VA facilities. This will have the following important implications: 1. Improve our understanding of the causes of cirrhosis in HIV-infected patients;2. Allow better stratification of the risk of cirrhosis, a diagnosis that is often made late when there is little chance of effective treatment;3. Provide a rationale for investigating whether medications recently studied for the treatment of fat redistribution in HALS also reduce HALS-related hepatic steatosis, necroinflammation and fibrosis and ultimately prevent the development of cirrhosis. 4. Identify specific antiretroviral medications strongly associated with cirrhosis which ought to be avoided in patients with evidence of substantial hepatic necroinflammation or fibrosis, in order to prevent progression to cirrhosis. 5. Ultimately, help reduce the burden of cirrhosis which is the second leading cause of death in HIV-infected persons.